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Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model

Acta Pharmacologica Sinica volume 45, pages 66–75 (2024)Cite this article

Abstract

Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) in glial cells, leading to the formation of glial cytoplasmic inclusions (GCI). We previous found that glial fatty acid-binding protein 7 (FABP7) played a crucial role in alpha-synuclein (αSyn) aggregation and toxicity in oligodendrocytes, inhibition of FABP7 by a specific inhibitor MF 6 reduced αSyn aggregation and enhanced cell viability in cultured cell lines and mouse oligodendrocyte progenitor cells. In this study we investigated whether MF 6 ameliorated αSyn-associated pathological processes in PLP-hαSyn transgenic mice (PLP-αSyn mice), a wildly used MSA mouse model with overexpressing αSyn in oligodendroglia under the proteolipid protein (PLP) promoter. PLP-αSyn mice were orally administered MF6 (0.1, 1 mg ·kg−1 ·d−1) for 32 days starting from the age of 6 months. We showed that oral administration of MF 6 significantly improved motor function assessed in a pole test, and reduced αSyn aggregation levels in both cerebellum and basal ganglia of PLP-αSyn mice. Moreover, MF 6 administration decreased oxidative stress and inflammation levels, and improved myelin levels and Purkinje neuron morphology in the cerebellum. By using mouse brain tissue slices and αSyn aggregates-treated KG-1C cells, we demonstrated that MF 6 reduced αSyn propagation to Purkinje neurons and oligodendrocytes through regulating endocytosis. Overall, these results suggest that MF 6 improves cerebellar functions in MSA by inhibiting αSyn aggregation and propagation. We conclude that MF 6 is a promising compound that warrants further development for the treatment of MSA.

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Fig. 1: MF 6 attenuates motor defects and αSyn aggregation in PLP-αSyn mice.
Fig. 2: MF 6 attenuates αSyn accumulation in Purkinje cells.
Fig. 3: MF 6 attenuates oxidative stress and inflammation levels of cerebellum.
Fig. 4: MF 6 rescued Purkinje cell dendritic branching in cerebellum.
Fig. 5: MF 6 blocked αSyn accumulation via endocytosis.
Fig. 6: Schematic representation of pathways underlying MF 6-mediated therapy in MSA.

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Data availability

The materials utilized in this investigation are obtainable through commercial means. The supporting data that validate the outcomes of this study are available within the article and accompanying materials. Figure 3a’s data were obtained from the publicly accessible Gene Expression Omnibus (GEO; GSE129531). The schematic diagrams utilized in this study were produced using Biorender (https://biorender.com/) under a publication license. Interested parties may contact the corresponding author to request the raw data used in this study.

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Acknowledgements

We would like to acknowledge the financial support provided by the Uehara Memorial Foundation, Japan Science and Technology Agency (JST) (grant number JPMJCR21P1), and Japan Agency for Medical Research and Development (AMED) (grant numbers JP20dm0107071; 04-2622). We also thank Amelia Sedjahtera of the Florey for genotyping each mouse, performing the behavioral experiments, and preparing the tissues for analysis. This research was funded by the Strategic Research Program for Brain Sciences, facilitated by the Japan Agency for Medical Research and Development (grant numbers JP20dm0107071 and 22ym0126095h0001). Additional support was provided by the Japan Society for the Promotion of Science through the KAKENHI Grant (22K06644).

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Author notes

  1. These authors contributed equally: An Cheng, Wenbin Jia.

Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    An Cheng, Wenbin Jia, Haoyang Wang, Takuya Sasaki, Ichiro Kawahata & Kohji Fukunaga

  2. Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA

    An Cheng

  3. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

    David I. Finkelstein

  4. Laboratory for Translational Neurodegeneration Research, Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, 6020, Innsbruck, Austria

    Nadia Stefanova

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Contributions

AC was responsible for data collection, data analysis, and original draft writing. Wenbin Jia conducted cell culture and staining experiments. DIF oversaw animal handling and behavior experiments. NS reviewed the manuscript and contributed to the methodology. HW performed brain slice experiments. TS contributed to the methodology and manuscript review. IK was responsible for the methodology. KF oversaw the supervision, project administration, funding, and manuscript review and editing. All authors critically reviewed and approved the final version of the manuscript. AC and KF verified the data and had the final responsibility for the decision to submit for publication.

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Correspondence to An Cheng or Kohji Fukunaga.

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Cheng, A., Jia, W., Finkelstein, D.I. et al. Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model. Acta Pharmacol Sin 45, 66–75 (2024). https://doi.org/10.1038/s41401-023-01138-y

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